Non-covalent interactions in receptor-ligand complexes. A study based on the electron charge density

Abstract

In this paper, we reported the results obtained by charge density analysis of the network of non‐covalent interactions (NCI) established in the binding pocket of a receptor, in relevant conformations of ligand – receptor complexes. Starting with strong and moderate hydrogen bonds, moving on to weaker polar interactions and ending with stacking and T‐shape like interactions between aromatic rings, all of them have been investigated within the framework of the density functional theory and the quantum theory of atoms in molecules. Also, natural bond orbital analysis was carried out, in order to evaluate quantitatively the electronic population of the aromatic rings. The analysis of our “case study” shows that the interactions of the catechol OH groups of the ligand, in the different conformations of the dopamine (DA) – D2 receptor complex, determine the decrease or increase of the electron density on the aromatic ring of DA. In turn, the electronic population of the aromatic ring of DA defines its orientation within the binding site and the type of interactions that it establishes with the aromatic rings of the receptor. Although the approach used here was traditionally applied to the study of NCI in small molecules complexes in gas phase, we show through this work that this methodology is also a very powerful tool for the study of biomolecular complexes, providing a very detailed description of the binding event. Copyright © 2013 John Wiley & Sons, Ltd.

Dopaminergic isoquinolines with hexahydrocyclopenta[ ij ]-isoquinolines as D 2 -like selective ligands

“…In general, the compounds herein studied displayed their pharmacophoric portions in a closely related spatial form to that reported for dopamine [17,34] and other dopaminergic ligands [35]. Consistently with previous experimental [36] and theoretical [37] data, the simulations indicated the relevance of negatively charged aspartate 114 and 103 for D 2 and D 1 DR ligand binding, respectively.…”

Halogen bonding in biological context: a computational study of D2 dopamine receptor

“…However, a more careful inspection of the intermolecular interactions at the substitution point reveals important differences in the interaction patterns. The charge density molecular graphs from Figures as well as previous results show that the ligand phenolic OH groups tend to act either as H‐bond donor against the hydroxyl oxygen of the serine residues in the binding pocket or to form oxygen‐oxygen interactions with them . On the other hand, the halogen rarely interacts with the hydroxyl oxygen of the serine residues.…”

“…Moreover, it has been proven that the sum of the ρ b values (∑ρ) for all the interactions established by the ligand molecule is a good measure of its anchoring strength to the binding pocket. Furthermore, the ∑ρ value corresponding to the interactions established by a particular group of atoms of the ligand molecule is a measure of the anchoring strength of that group to the binding pocket . The ability to decompose the interaction energy in contributions by atom or group of atoms makes the QTAIM analysis particularly useful in analysis, design and optimization of ligand molecules.…”

Molecular insight into the interaction mechanisms of amino-2H -imidazole derivatives with BACE1 protease: A QM/MM and QTAIM study

“…There are many works discussing this interesting problem in the literature. Our own studies have demonstrated the importance to include QTAIM analysis to solve these intricacies . Thus, in the next step of our study we performed a QTAIM study of these complexes using B3LYP‐D/6‐31G(d) calculations.…”

“…As the noncovalent interactions generally are weaker than the covalent ones, it is evident that they are more difficult to be properly described. However, recent advances in computational calculation of the electron charge density have made possible the proper description of the three‐dimensional network of bonding and nonbonding interactions in different biological systems in the context of the quantum theory of atoms in molecules (QTAIM) . Thus, it is now possible to study more accurately the effects of substitutes ligands (bearing small structural modifications) when they interact with their biological receptor.…”